A multilamellar or onion-like vesicle is an enclosed structure always self-assembled by multiple polymer bilayers. Compared with the unilamellar vesicle, onion-like vesicles show more complex functionality and better structural stability, making onion-like vesicles have better and more applications in drug and gene delivery. On the other hand, polymerizationinduced self-assembly (PISA) is an improved polymer self-assembly strategy that can significantly increase preparation efficiency. Therefore, using the PISA strategy to prepare onion-like vesicles can further increase their commercial application potential. Herein, we show computer evidence that comb-like copolymers can self-assemble into the onion-like vesicle by PISA. The influence of rigidity, degree of polymerization, and structural symmetry of the macromolecular chain transfer agent (macro-CTA) on the morphology transformation is explored in our work. At the same time, we find the hollow onion-like vesicle and the solid onion-like vesicle can be synthesized by regulating the structural symmetry of macro-CTA, and the formation ways are different. Finally, we develop design guidelines of comb-like copolymers for preparing the onion-like vesicle by PISA, which can be exploited for drug and gene delivery applications.